| 1. |
- Nilsson, Magnus, et al.
(författare)
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Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma
- 2022
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Ingår i: Drug Design, Development and Therapy. - : Informa Healthcare. - 1177-8881. ; 16, s. 2901-2917
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 mu g/kg and AZD4604 at 30 mu g/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.
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| 2. |
- Bergström, Christel A. S., et al.
(författare)
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Early pharmaceutical profiling to predict oral drug absorption : Current status and unmet needs
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 57, s. 173-199
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Tidskriftsartikel (refereegranskat)abstract
- Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.
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| 3. |
- Bordé, P., et al.
(författare)
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Transiting exoplanets from the CoRoT space mission: XXIX. The hot Jupiters CoRoT-30 b and CoRoT-31 b
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 635
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery as well as the orbital and physical characterizations of two new transiting giant exoplanets, CoRoT-30 b and CoRoT-31 b, with the CoRoT space telescope. Methods. We analyzed two complementary data sets: photometric transit light curves measured by CoRoT, and radial velocity curves measured by the HARPS spectrometer. To derive the absolute masses and radii of the planets, we modeled the stars from available magnitudes and spectra. Results. We find that CoRoT-30 b is a warm Jupiter on a close-to-circular 9.06-day orbit around a G3V star with a semi-major axis of about 0.08 AU. It has a radius of 1.01 ± 0.08 RJ, a mass of 2.90 ± 0.22 MJ, and therefore a mean density of 3.45 ± 0.65 g cm-3. The hot Jupiter CoRoT-31 b is on a close-to-circular 4.63-day orbit around a G2 IV star with a semi-major axis of about 0.05 AU. It has a radius of 1.46 ± 0.30 RJ, a mass of 0.84 ± 0.34 MJ, and therefore a mean density of 0.33 ± 0.18 g cm-3. Conclusions. Neither system seems to support the claim that stars hosting planets are more depleted in lithium. The radii of both planets are close to that of Jupiter, but they differ in mass; CoRoT-30 b is ten times denser than CoRoT-31 b. The core of CoRoT-30 b would weigh between 15 and 75 Earth masses, whereas relatively weak constraints favor no core for CoRoT-31 b. In terms of evolution, the characteristics of CoRoT-31 b appear to be compatible with the high-eccentricity migration scenario, which is not the case for CoRoT-30 b. The angular momentum of CoRoT-31 b is currently too low for the planet to evolve toward synchronization of its orbital revolution with stellar rotation, and the planet will slowly spiral-in while its host star becomes a red giant. CoRoT-30 b is not synchronized either: it looses angular momentum owing to stellar winds and is expected reach steady state in about 2 Gyr. CoRoT-30 and 31, as a pair, are a truly remarkable example of diversity in systems with hot Jupiters.
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| 4. |
- Deleuil, M., et al.
(författare)
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Planets, candidates, and binaries from the CoRoT/Exoplanet programme: The CoRoT transit catalogue
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 619
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Tidskriftsartikel (refereegranskat)abstract
- The CoRoT space mission observed 163 665 stars over 26 stellar fields in the faint star channel. The exoplanet teams detected a total of 4123 transit-like features in the 177 454 light curves. We present the complete re-analysis of all these detections carried out with the same softwares so that to ensure their homogeneous analysis. Although the vetting process involves some human evaluation, it also involves a simple binary flag system over basic tests: Detection significance, presence of a secondary, difference between odd and even depths, colour dependence, V-shape transit, and duration of the transit. We also gathered the information from the large accompanying ground-based programme carried out on the planet candidates and checked how useful the flag system could have been at the vetting stage of the candidates. From the initial list of transit-like features, we identified and separated 824 false alarms of various kind, 2269 eclipsing binaries among which 616 are contact binaries and 1653 are detached ones, 37 planets and brown dwarfs, and 557 planet candidates. We provide the catalogue of all these transit-like features, including false alarms. For the planet candidates, the catalogue gives not only their transit parameters but also the products of their light curve modelling: Reduced radius, reduced semi-major axis, and impact parameter, together with a summary of the outcome of follow-up observations when carried out and their current status. For the detached eclipsing binaries, the catalogue provides, in addition to their transit parameters, a simple visual classification. Among the planet candidates whose nature remains unresolved, we estimate that eight (within an error of three) planets are still to be identified. After correcting for geometric and sensitivity biases, we derived planet and brown dwarf occurrences and confirm disagreements with Kepler estimates, as previously reported by other authors from the analysis of the first runs: Small-size planets with orbital period less than ten days are underabundant by a factor of three in the CoRoT fields whereas giant planets are overabundant by a factor of two. These preliminary results would however deserve further investigations using the recently released CoRoT light curves that are corrected of the various instrumental effects and a homogeneous analysis of the stellar populations observed by the two missions.
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| 5. |
- Govender, Rydvikha, 1989, et al.
(författare)
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Independent tailoring of dose and drug release via a modularized product design concept for mass customization
- 2020
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 12:8, s. 1-24
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Tidskriftsartikel (refereegranskat)abstract
- Independent individualization of multiple product attributes, such as dose and drug release, is a crucial overarching requirement of pharmaceutical products for individualized therapy as is the unified integration of individualized product design with the processes and production that drive patient access to such therapy. Individualization intrinsically demands a marked increase in the number of product variants to suit smaller, more stratified patient populations. One established design strategy to provide enhanced product variety is product modularization. Despite existing customized and/or modular product design concepts, multifunctional individualization in an integrated manner is still strikingly absent in pharma. Consequently, this study aims to demonstrate multifunctional individualization through a modular product design capable of providing an increased variety of release profiles independent of dose and dosage form size. To further exhibit that increased product variety is attainable even with a low degree of product modularity, the modular design was based upon a fixed target dosage form size of approximately 200 mm3 comprising two modules, approximately 100 mm3 each. Each module contained a melt-extruded and molded formulation of 40% w/w metoprolol succinate in a PEG1500 and Kollidon® VA64 erodible hydrophilic matrix surrounded by polylactic acid and/or polyvinyl acetate as additional release rate-controlling polymers. Drug release testing confirmed the generation of predictable, combined drug release kinetics for dosage forms, independent of dose, based on a product’s constituent modules and enhanced product variety through a minimum of six dosage form release profiles from only three module variants. Based on these initial results, the potential of the reconfigurable modular product design concept is discussed for unified integration into a pharmaceutical mass customization/mass personalization context.
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| 6. |
- Sjöberg, Åsa, et al.
(författare)
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Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique
- 2013
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Ingår i: European Journal of Pharmaceutical Sciences. - Amsterdam : Elsevier B.V. - 0928-0987 .- 1879-0720. ; 48:1-2, s. 166-180
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism. Data on viability, correlation between apparent permeability coefficients (Papp) and fraction absorbed (fa) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors. Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally. Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER). Intestinal metabolism was studied using testosterone and midazolam as probe substrates.There was a steep sigmoidal correlation between Papp in the Ussing chamber, using jejunal segments, and oral fa in humans, for a set of 25 drugs (R2: 0.85, p < 0.01). A clear sigmoidal relationship was also obtained between Papp in colonic segments and fa after colonic administration in humans for a set of 10 drugs (R2: 0.93, p < 0.05). Regional permeability data showed a tendency for highly permeable compounds to have higher or similar Papp in colon as in the small intestinal segments, while the colonic regions showed a lower Papp for more polar compounds as well as for d-glucose and l-leucine. Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux- and uptake asymmetry. Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam.In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (fa), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man. Furthermore, a sigmoidal relationship of Papp vs. fa was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R2: 0.83, p < 0.01). The correlation curve reported can be used by any laboratory for predictions of human permeability and fa. In addition, for the first time a correlation curve between colonic Papp and human colonic fa is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates. © 2012 Elsevier B.V. All rights reserved.
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